There have been tremendous advances in the field of autoimmunity in the last 20 years, and our understanding of the mechanisms underlying autoimmune disease has grown exponentially. True tolerance is likely to arise not from improved immunosuppression, but from improved understanding of the normal mechanisms which generate and maintain self-tolerance and the ability to manipulate these mechanisms for the prevention and treatment of autoimmune diseases. The mechanisms of autoimmunity that underlie many diseases are similar and an integrated multi-specialty approach for evaluating new and emerging therapies would provide the opportunity to integrate knowledge from the various specialties. We have chosen to study therapy of autoimmune disease by blocking co- stimulatory signals. This strategy has 2 advantages. First, these are antigen non-specific steps in T cell activation and immune responses. This means that tolerance can be achieved without needing to know the identity of the antigen. Second, restricted delivery of signal 2 and alteration in cytokine production and profiles are probably involved in normal mechanisms of self-tolerance. We will focus on the CD40-CD40L pathway. The human diseases that our program will focus on are multiple sclerosis (MS), inflammatory bowel disease (IBD), and psoriasis. All are organ specific diseases where T cells appear to be essential in initiating the immune response and lead to the particular disease pathology. The overall goals of project #1 are to study in a pilot trial the efficacy and safety of anti-CD40L therapy in MS. The goals of project #2 are to study in a pilot trial the efficacy and safety of anti-CD40L therapy in IBD. Project #3 will focus on the immunologic changes associated with anti- CD40L therapy in patients with MS and IBD. Project #4 will study the immune mechanisms of psoriasis. The approach of treating autoimmune diseases by blocking secondary signal of T cell activation is timely and has a high likelihood of success. There is a body of evidence supporting the use of anti-CD40L in autoimmune disease. The data obtained from the pilot trials will be valuable in designing phase III clinical trials, while the immunologic investigations will help identify surrogate markers for disease activity.